This collaborative application is submitted in response to RFA-HG-09-014 and represents the effort of the NIDDK IBD Genetics Consortium. Despite great heritability, the root causes of Inflammatory Bowel Disease (IBD) (Crohn's Disease and Ulcerative Colitis) remain unknown, limiting efforts to prevent and treat disease. Recent efforts, particularly through genome-wide association studies, have successfully identified many loci involved in disease. While a few novel components of disease biology have been provided (e.g., autophagy), insights from these loci have been limited by challenges of conclusively determining specific causal variants, the genes they impact and the relevant functional alterations they introduce. Furthermore, these variants, even in combination, explain only a small fraction of the heritability, suggesting that additional (likely unexplored rarer) variation plays a significant role in pathogenesis and heritability. We therefore propose to deeply sequence all genes near the more than 50 genome-wide significant associations in IBD to discover rare variants that are associated with IBD. Using samples already in an NIDDK sponsored repository and scanned in our successful GWAS, we propose to work closely with a large scale sequencing center to collect deep sequence data on all coding exons and proximal untranslated and promoter regions. In total, more than 5,000 samples will be sequenced in this project (including more than 500 African-American cases and 200 extremely early onset cases that will likely expand the range of causal variants discovered). We further aim to develop new analytical tools for the statistical analysis of rare variants. Our proposed approach involves likelihood-based techniques that combine information across a target region to detect weak signals that inevitably arise from the mixture of neutral, risk and protective variants that may be found in associated genes. By using these data efficiently, we aim to conclusively identify which genes harbor individual variants and/or collections of rare DNA variants that significantly predispose to or protect from IBD, and thus translate the abstract heritability into solid biological clues to disease pathogenesis that can be studied molecularly and approached therapeutically. These efforts and their follow-up, which will be performed on thousands of IBD patients collected by the NIDDK research groups and being provided with phenotype data to NIH repositories, will form the cornerstone of IBD genetic and functional research going forward. PUBLIC HEALTH RELEVANCE: This research aims to document a large set of variants associated to IBD risk across both pediatric and adult cases and across cases with diverse ethnicities. The discovered variants will considerably increase our understanding of the biological basis of disease and thereby open new avenues to treatment and prevention.